(3r) epimer of octahydro-7,7-dimethyl-8-methylene 1h-3a, 6-methanoazulen-3-yl acetate, composition, synthesis process and use of said epimer

ABSTRACT

The first subject matter of the invention is the (3R) epimer of octahydro-7,7-dimethyl-8-methylene-1H-3a, 6-methanoazulen-3-yl acetate [(octahydro-7,7-dimethyl-8-methylene-[3R,3aR,6R,8aR]-1H-3a,6-methanoazulen-3-yl acetate) or (R)-norzizaenylacetate] of formula I (I). The subject matter of the invention is also compositions comprising (R)norzizaenyl acetate and also a novel synthesis process and the use of said ester.

The invention relates primarily to the (3R)-epimer of octahydro-7,7-dimethyl-8-methylene-1H-3a,6-methanoazulene-3-yl acetate (octahydro-7,7-dimethyl-8-methylene-[3R,3aR,6R,8aR]-1H-3a,6-methanoazulene-3-yl acetate) with formula

also referred to herein as (R)-ziza-6(13)-en-12-yl acetate.

The invention also relates to compositions with (R)-ziza-6(13)-en-12-yl acetate, as well as a new synthesis method and use of said ester.

The term “Vetiver” designates in French the plants of the Poaceae (grasses) family. They consist of several species of de Chrysopogon (formerly Vetiveria) genus. A dozen species growing in tropical areas are known. The best known species is Chrysopogon zizanioides, which grows primarily in the Indian subcontinent. Two other species are frequently grown: Chrysopogon nigritanus in Southern Africa and Chrysopogon nemoralis in Southeast Asia.

The plant grows as large green tufts, and has roots, which grow vertically, that can reach depths of up to three meters (10 ft).

After distillation, the Vetiver roots produce a highly viscous essential oil used in perfumery. Vetiver essential oil belongs to the woody olfactory family. Vetiver essence is a fine and complex fragrance: woody, aromatic, green, earthy, sometimes slightly smoky or citrus-like.

Many fragrances on the market contain Vetiver essential oil, or derivatives thereof, as the key aromatic ingredient.

Studies conducted by the applicant on different Vetiver extracts, components, and derivatives have identified a number of main compounds that have an aromatic impact. Among these molecules affecting aroma, those having a zizaane backbone occupy a special place, including khusimone, whose structure corresponds to the formula II below

which is known as the main aromatic ingredient in Vetiver. This substance has a woody odor, typical of Vetiver and reminiscent of the smell of Vetiver oil.

Vetiver essential oil of contains multiple components as shown by Weyerstahl's publications (see, for example, P. Weyerstahl et al., Flavour and Fragrance Journal, 2000, 15, 395-412.) There are, in particular, ketones and alcohols. But Vetiver oil naturally contains very little or no acetate.

Analytical work completed by the applicant has outlined the essential contribution of (R)-ziza-6(13)-en-12-yl acetate with formula I

that is a compound that has an important aromatic impact, with a woody note typical of Vetiver, very similar to that of khusimone. In the same work, it was possible to determine that its (3S)-epimer had a much lower aromatic profile.

At present, no synthetic aromatic material corresponding to (R)-ziza-6(13)-en-12-yl acetate is commercially available. The lack of a synthetic substitute is partly due to the complex nature of sesquiterpenes which comprise the essence of Vetiver and its derivatives.

In the previous art, reference CAS: 52771-08-1, called octahydro-7,7-dimethyl-8-methylene-1H-3a,6-methanoazulene-3-yl acetate is mentioned without any further clarification as to the isometric form of this compound (FR 2201841).

Likewise, the (3S)-epimer of octahydro-7,7-dimethyl-8-methylene-1 H-3a,6-methanoazulene-3-yl acetate (octahydro-7,7-dimethyl-8-methylene-[3S,3aR,6R,8aR]-1H-3a,6-methanoazulene-3-yl acetate), otherwise referred to herein as (S)-ziza-6(13)-en-12-yl acetate) is known (CAS No. 124601-88-3) (Sakurai Kazutoshi et al., Agricultural and Biological Chemistry, Japan Soc. For Bioscience, Biotechnology and Agrochem, Tokyo, JP, vol. 53, no. 5, 1989-05-23, pages 1449-1450).

However, the (3R)-epimer of octahydro-7,7-dimethyl-8-methylene-1H-3a, 6-methanoazulene-3-yl acetate [octahydro-7,7-dimethyl-8-methylene-[3S, 3aR,6R,8aR]-1H-3a,6-methanoazulene-3-yl acetate, or (S)-ziza-6(13)-en-12-yl acetate] has never been isolated or synthesized, especially in pure or substantially pure isometric form, that is, as the (R)-isomer to over 95%.

After extensive research, the applicant has now developed a new 2-step synthesis method for (R)-ziza-6(13)-en-12-yl acetate from khusimone.

Thus, the invention relates primarily to the (3R)-epimer of octahydro-7, 7-dimethyl-8-methylene-1H-3a,6-methanoazulene-3-yl acetate [(octahydro-7, 7-dimethyl-8-methylene-[3R,3aR,6R,8aR]-1H-3a,6-methanoazulene-3-yl acetate) or (R)-ziza-6(13)-en-12-yl acetate] with formula I

In one embodiment of the invention said compound is isolated.

By isolated it is understood that the solution containing said compound with formula 1 has undergone at least one purification step of such compound.

The invention also relates to a composition with at least (R)-ziza-6(13)-en-12-yl acetate.

In a first embodiment of the invention the composition can only contain the (R) form of ziza-6(13)-en-12-yl acetate [(R)-ziza-6(13)-en-12-yl acetate] and therefore does not contain the (S)-ziza-6(13)-en-12-yl acetate form, regardless of the amount of ziza-6(13)-en-12-yl acetate in the composition.

In another embodiment of the invention the composition can contain (R)-ziza-6(13)-en-12-yl acetate (S)-ziza-6(13)-en-12-yl acetate in a weight ratio of the (R)-ziza-6(13)-en-12-yl acetate form to the (S)-ziza-6(13)-en-12-yl acetate form, [(R)/(S)], _(g)reater than 1.2, preferably greater than 1.5, regardless of the total amount of ziza-6(13)-en-12-yl acetate in the composition.

The invention also relates to a new synthesis method of (R)-ziza-6(13)-en-12-yl acetate (Formula I) by khusimone reduction (Formula II) in the presence of an organic solvent, followed by acetylation of the resulting alcohol (12-nor-ziza-6(13)-en-2β-ol, Formula III) in the presence of a base, a nucleophilic catalyst and an aprotic solvent, according to the following reaction sequence.

The new synthesis method proposed herein has the advantage, besides its simplicity, its relatively low cost and the possibility of industrialization, of allowing the synthesis of (R)-ziza-6(13)-en-12-yl acetate in a pure or nearly pure form. By pure or nearly pure, it is understood herein that at the end of the reaction, the reaction medium contains very little or virtually no (S)-epimer [(S)-ziza-6(13)-en-12-yl acetate].

In fact, experience shows that it is possible to obtain, in two steps, up to 95% or even 98.5% of the (R)-form of ziza-6(13)-en-12-yl acetate in the reaction medium (see Example 1).

Therefore, the invention relates to a synthesis method of (R)-ziza-6(13)-en-12-yl acetate, comprised of a first step, the reduction of khusimone in the presence of a reducing agent and an organic solvent, and a second step, the acetylation of the product obtained in the first step in the presence of an organic solvent.

More specifically, the first step of the method, according to the invention, the reduction reaction of khusimone can be carried out in the presence of a reducing agent which can be selected from lithium aluminum hydride (LiAlH₄), DiBAH (diisobutylaluminium hydride), sodium borohydride (NaBH₄), lithium borohydride (NaLiH₄) or potassium borohydride (KBH₄). Preferably, according to the invention, NaBH₄ can be used.

According to the invention, the reduction reaction of khusimone can be carried out with a molar ratio [(AR)/(K)] between the reducing agent (RA) and the khusimone (K) that can be between 0.5 and 5, preferably between 1 and 3, more preferably equal to 2.

According to the invention, the reduction reaction of khusimone can be carried out in the presence of an organic solvent which can be selected from methanol (MeOH), ethanol (EtOH), propanol, isopropanol, n-butanol, sec-butanol, isobutanol, t-butanol, tetrahydrofuran (THF), 1,4-dioxane, dimethylsulfoxide (DMSO), acetonitrile, or mixtures in all proportions of these solvents, for example, DMSO/MeOH, THF/MeOH, DMSO/THF, DMSO/dioxane mixtures. Preferably, according to the invention, the organic solvent can be ethanol.

According to the invention, the reduction of khusimone can be carried out at a temperature between −25 ° C. and the solvent reflux temperature. Preferably, the reaction can be started at a temperature between −25° C. and 25° C. (13° F. to 77° F.), more preferably −25° C. and 0° C. (13° F. to 32° F.). The reaction can then progress freely until it reaches solvent reflux temperature; it can then be kept at a temperature between 25° C. (77° F.) and the reflux temperature, until all reactants are exhausted. Most preferably, once the solvent reflux temperature has been reached, the reaction can be kept at this temperature.

Those of ordinary skill in the art will readily stop the reaction when it can be observed, by sample collection and analysis, that the reaction has reached the desired stage, for example, by measuring the removal of khusimone with gas chromatography or thin layer chromatography, or nuclear magnetic resonance.

According to the invention, the 12-nor-ziza-6(13)-en-2β-ol (formula III) obtained in the first step can be directly converted into (R)-ziza-6(13)-en-12-yl acetate (formula I) by acetylation by reacting said 12-nor-ziza-6(13)-en-2β-ol with an acetylating agent (Ac) that can be selected from acetic anhydride, acetic acid, or acetyl chloride, in the presence of a base and a nucleophilic catalyst in an aprotic solvent.

According to the invention, the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol can be carried out with a molar ratio [(Ac)/(Z)] between the acetylating agent (Ac) and 12-nor-ziza-6(13)-en-2β-ol (Z) that can be between 1 and 5, preferably equal to 1.5.

According to the invention, the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol can be carried out in the presence of an organic base that can be selected from N,N-Diisopropylethylamine (DIPEA), triethylamine (Et₃N) or pyridine. Preferably, the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol can be carried out in the presence of triethylamine.

According to the invention, the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol can be carried out with a molar ratio [(OB)/(Z)] between the organic base (OB) and the 12-nor-ziza-6(13)-en-2β-ol (Z) that can be between 0.1 and 5, preferably equal to 1.5.

According to the invention, the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol can be carried out in the presence of an organic base that can be selected from 4-(N,N-Dimethylam ino)pyridine (DMAP), 1,4-Diazabicyclo[2.2.2]octane (DABCO), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) or N,N′-Dicyclohexylcarbodiimide (DCC). Preferably, according to the invention, DMAP can be used.

According to the invention, the acetylation reaction of 12-nor-ziza-6(13)-en-26-ol can be carried out with a molar ratio [(NC)/(Z)] between the nucleophilic catalyst (NC) and the 12-nor-ziza-6(13)-en-2β-ol (Z) that can be between 0.01 and 10, preferably equal to 0.1.

According to the invention, the acetylation reaction of 12-nor-ziza-6(13)-en-26-ol can be carried out in the presence of an aprotic solvent that can be selected from n-hexane, cyclohexane, 1,4-dioxane, dichloromethane (DCM), carbon tetrachloride (CCl₄), benzene, trichlorethylene (Cl₂C═CHCl), tetrachlorethylene (Cl₂C═CCl₂), toluene, carbon disulfide (CS₂) diethyl ether (Et₂O), chloroform (CHCl₃), bromobenzene (PhBr), chlorobenzene (PhCl), ethyl acetate (AcOEt), the dimethyl ether (DME), tetrahydrofuran (THF), 1,1-dichloroethane (C₂H₄Cl₂), 1,2-dichloroethane (DCE), pyridine, butanone, acetone, acetic anhydride (Ac₂O), tetramethylurea ((Me₂N)₂CO), benzonitrile (PhCN), propionitrile (CH₃CH₂CN), hexamethylphosphoramide (HMPA), nitrobenzene (PhNO₂), nitromethane (MeNO₂), dimethylformamide (DMF), acetonitrile (MeCN), sulfolane, dimethylsulfoxide (DMSO), formamide (HCONH₂), N-methylformamide (NMF), N-methylacetamide (CH₃CONHMe), acetic acid.

Preferably, according to the invention, the aprotic solvent can be dichloromethane.

According to the invention, the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol can be carried out at a temperature between −25 ° C. and the solvent reflux temperature. Preferably, the reaction can be started at a temperature between −25° C. and 25° C. (13° F. to 77° F.), more preferably −25° C. and 0° C. (13° F. to 32° F.). The reaction can then progress freely until it reaches solvent reflux temperature; it can then be kept at a temperature of about 25° C. (77° F.), until all reactants are exhausted.

Those of ordinary skill in the art will readily stop the reaction when it can be observed, by sample collection and analysis, that the reaction has reached the desired stage, for example, by measuring the removal of 12-nor-ziza-6(13)-en-2β-ol with gas chromatography or thin layer chromatography, or nuclear magnetic resonance.

The invention also relates to (R)-ziza-6(13)-en-12-yl acetate, with Formula I, which can be obtained from the synthesis method, according to the invention.

The invention further relates to the use of (R)-ziza-6(13)-en-12-yl acetate, as a fragrance agent. Preferably, the fragrance agent may be intended as an ingredient in any kind of composition such as a perfume, an eau de partum, eau de toilette, hygiene products, cosmetics, soaps, detergents or candles.

According to the invention, (R)-ziza-6(13)-en-12-yl acetate can be used alone in compositions, that is, without the(S)-ziza-6(13)-en-12-yl acetate form, or in the presence of (S)-ziza-6(13)-en-12-yl in a weight ratio of the (R)-ziza-6(13)-en-12-yl acetate form to the (S)-ziza-6(13)-en-12-yl acetate form (R/S) greater than 1.2, preferably greater than 1.5.

Other invention features and advantages will emerge from the following examples, given as illustrations, but not by way of limitation, as well as from FIG. 1, which represents the gas chromatography analysis results of the synthesis reaction of (R)-ziza-6(13)-en-12-yl acetate from khusimone.

Thus, FIG. 1 shows the chromatogram obtained by gas chromatography analysis of the product resulting at the end of the two steps synthesis described in Examples 1 and 2.

EXAMPLES Example 1 Synthesis of (R)-ziza-6(13)-en-12-yl Acetate from Khusimone

Step 1: Synthesis of 12-nor-ziza-6(13)-en-2β-ol from Khusimone

In a flask, 3 mmol of khusimone are added in the presence of 6 mmol of sodium borohydride in 30 mL of ethanol to obtain a khusimone concentration 0.1 M, at room temperature for 2 h. The solvent is then evaporated in vacuum and 10 ml of dichloromethane are added to the reaction mixture. Next, 10 mL of 1 N hydrochloric acid are added. Following decantation, the organic phase is recovered and washed with brine, and finally dried over magnesium sulfate. After solvent evaporation, the product is obtained as a colorless oil with a 97% yield.

Step 2: Synthesis of (R)-ziza-6(13)-en-12-yl Acetate from 12-nor-ziza-6(13)-en-2β-ol.

The product obtained in step 1 is mixed with acetic anhydride (2 equivalents), triethylamine (1.2 equivalents) and 4-dimethylaminopyridine (0.1 equivalents) in 10 mL of dichloromethane at room temperature for 2 h. The reaction mixture was washed with a 0.1 N hydrochloric ac, of and finally with brine. After drying over magnesium sulfate and solvent evaporation, the product is obtained as a colorless oil which crystallizes spontaneously. The reaction yield increases to 83% for (R)-ziza-6(13)-en-12-yl acetate, with a purity of 98.5%.

The result of this synthesis is shown in FIG. 1, appended, wherein can be seen the chromatogram obtained by gas chromatography of the product obtained at the end of the 2 synthesis steps, shown at the top of the figure.

Total removal of the starting material (khusimone) can be observed, as well as the presence of an important peak that reveals the presence of (R)-ziza-6(13)-en-12-yl acetate, representing 98.5% by quantity of the total amount of (R) and (S) ziza-6(13)-en-12-yl acetate obtained. The presence of a minor peak can also be observed, which shows the presence of (S)-ziza-6(13)-en-12-yl acetate and represents less than 1.5% by quantity of the total amount of (R) and (S) ziza-6(13)-en-12-yl acetate obtained.

Identification of the different compounds was made by mass spectrometry, as well as by nuclear magnetic resonance after isolation of said compounds. 

1. (3R)-epimer of octahydro-7,7-dimethyl-8-methylene-1H-3a, 6-methanoazulene-3-yl acetate [(octahydro-7,7-dimethyl-8-methylene-[3R, 3aR,6R,8aR]-1H-3a,6-methanoazulene-3 -yl acetate) or (R)-ziza-6(13)-en-12-yl acetate] with formula I


2. (R)-ziza-6(13)-en-12-yl acetate of claim 1 was isolated.
 3. Composition containing (R)-ziza-6(13)-en-12-yl acetate at least, with formula I.
 4. Composition according to claim 3, characterized by containing ziza-6(13)-en-12-yl acetate in its (R) form only [100% (R)-ziza-6(13)-en-12-yl acetate] and does not contain ziza-6(13)-en-12-yl acetate in its (S) form [0% (S)-ziza-6(13)-en-12-yl acetate].
 5. Composition according to claim 3, characterized by containing (R)-ziza-6(13)-en-12-yl acetate and (S)-ziza-6(13)-en-12-yl acetate in a weight ratio of the (R)-ziza-6(13)-en-12-yl acetate form to the (S)-ziza-6(13)-en-12-yl acetate form [(R)/(S)] greater than 1.2, preferably greater than 1.5.
 6. Synthesis method of (R)-ziza-6(13)-en-12-yl acetate, with formula 1, comprised of a first step, the reduction of khusimone in the presence of a reducing agent and an organic solvent, and a second step, the acetylation of the product obtained in the first step in the presence of an organic solvent.
 7. Method of claim 6 characterized by the reducing agent being selected from lithium aluminum hydride (LiAlH₄), DiBAH (diisobutylaluminium hydride), sodium borohydride (NaBH₄), lithium borohydride (NaLiH₄) or potassium borohydride (KBH₄), preferably sodium borohydride.
 8. Method of claim 6, characterized by the molar ratio [(AR)/(K)] between the reducing agent (RA) and the khusimone (K) being between 0.5 and 5, preferably between 1 and 3, more preferably equal to
 2. 9. Method of claim 6, characterized by the organic solvent being selected from methanol (MeOH), ethanol, propanol, isopropanol, n-butanol, sec-butanol, isobutanol, t-butanol, tetrahydrofuran (THF), 1,4-dioxane, dimethylsulfoxide (DMSO), acetonitrile, or mixtures in all proportions of these solvents, for example, DMSO/methanol, THF/methanol, DMSO/THF, DMSO/dioxane mixtures.
 10. Method of claim 6, characterized by the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol being carried out by reacting 12-nor-ziza-6(13)-en-2β-ol with an acetylating agent (Ac) in the presence of a base and a nucleophilic catalyst in an aprotic solvent.
 11. Method of claim 10, characterized by the acetylating agent (Ac) being selected from acetic anhydride, acetic acid, or acetyl chloride.
 12. Method of claim 11, characterized by the molar ratio [(Ac)/(Z)] between the acetylating agent (Ac) and 12-nor-ziza-6(13)-en-2β-ol (Z) being between 1 and 5, preferably equal to 1.5.
 13. Method of claim 10, characterized by the organic base being selected from N,N-Diisopropylethylamine (DIPEA), triethylamine (Et₃N) or pyridine, preferably triethylamine.
 14. Method of claim 13, characterized by the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol being carried out with a molar ratio [(OB)/(Z)] between the organic base (OB) and the 12-nor-ziza-6(13)-en-2β-ol (Z) of 0.1 to 5, preferably equal to 1.5.
 15. Method of claim 10, characterized by the nucleophilic catalyst being selected from 4-(N,N-Dimethylamino)pyridine (DMAP), or from 1,4-Diazabicyclo[2.2.2]octane (DABCO), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) or N,N′ -Dicyclohexylcarbodiimide (DCC), preferably, according to the invention, it will be possible to use (DMAP).
 16. Method of claim 15, characterized by the acetylation reaction of 12-nor-ziza-6(13)-en-2β-ol being carried out with a molar ratio [(NC)/(Z)] between the nucleophilic catalyst (NC) and the 12-nor-ziza-6(13)-en-2β-ol (Z) of 0.01 to 10, preferably equal to 0.1.
 17. Method of claim 10, characterized by the aprotic solvent being selected from n-hexane, cyclohexane, 1,4-dioxane, dichloromethane (DCM), carbon tetrachloride (CCI₄), benzene, trichlorethylene (Cl₂C═CHCl), tetrachlorethylene (Cl₂C═CCl₂), toluene, carbon disulfide (CS₂) diethyl ether (Et₂O), chloroform (CHCl₃), bromobenzene (PhBr), chlorobenzene (PhCl), ethyl acetate (AcOEt), the dimethyl ether (DME), tetrahydrofuran (THF), 1,1-dichloroethane (C₂H₄Cl₂), 1,2-dichloroethane (DCE), pyridine, butanone, acetone, acetic anhydride (Ac₂O), tetramethylurea ((Me₂N)₂CO), benzonitrile (PhCN), propionitrile (CH₃CH₂CN), hexamethylphosphoramide (HMPA), nitrobenzene (PhNO₂), nitromethane (MeNO₂), dimethylformamide (DMF), acetonitrile (MeCN), sulfolane , dimethylsulfoxide (DMSO), formamide (HCONH₂), N-methylformamide (NMF), N-methylacetamide (CH₃CONHMe), acetic acid, preferably dichloromethane.
 18. (R)-ziza-6(13)-en-12-yl acetate, with formula 1, which can be obtained from the synthesis method, according to the invention.
 19. A fragrance agent comprising (R)-ziza-6(13)-en-12-yl acetate as a fragrance agent.
 20. The fragrance agent according to claim 19, characterized by (R)-ziza-6(13)-en-12-yl acetate being alone, without the (S)-ziza-6(13)-en-12-yl form, or in the presence of the (S)-ziza-6(13)-en-12-yl form, in a weight ratio of the (R)-ziza-6(13)-en-12-yl acetate form to the (S)-ziza-6(13)-en-12-yl acetate form (R/S) greater than 1.2, preferably greater than 1 5, preferably greater than 1.5. 